Liquid-biopsy proteomics combined with AI identifies cellular drivers of eye aging and disease in vivo.

Single-cell analysis in living humans is essential for understanding disease mechanisms, but it is impractical in non-regenerative organs, such as the eye and brain, because tissue biopsies would cause serious damage. We resolve this problem by integrating proteomics of liquid biopsies with single-cell transcriptomics from all known ocular cell types to trace the cellular origin of 5,953 proteins detected in the aqueous humor. We identified hundreds of cell-specific protein markers, including for individual retinal cell types. Surprisingly, our results reveal that retinal degeneration occurs in Parkinson's disease, and the cells driving diabetic retinopathy switch with disease stage. Finally, we developed artificial intelligence (AI) models to assess individual cellular aging and found that many eye diseases not associated with chronological age undergo accelerated molecular aging of disease-specific cell types. Our approach, which can be applied to other organ systems, has the potential to transform molecular diagnostics and prognostics while uncovering new cellular disease and aging mechanisms.

Liquid Biopsy Proteomics in Ophthalmology.

Minimally invasive liquid biopsies from the eye capture locally enriched fluids that contain thousands of proteins from highly specialized ocular cell types, presenting a promising alternative to solid tissue biopsies. The advantages of liquid biopsies include sampling the eye without causing irreversible functional damage, potentially better reflecting tissue heterogeneity, collecting samples in an outpatient setting, monitoring therapeutic response with sequential sampling, and even allowing examination of disease mechanisms at the cell level in living humans, an approach that we refer to as TEMPO (Tracing Expression of Multiple Protein Origins). Liquid biopsy proteomics has the potential to transform molecular diagnostics and prognostics and to assess disease mechanisms and personalized therapeutic strategies in individual patients. This review addresses opportunities, challenges, and future directions of high-resolution liquid biopsy proteomics in ophthalmology, with particular emphasis on the large-scale collection of high-quality samples, cutting edge proteomics technology, and artificial intelligence-supported data analysis.

Ocular Neovascular Conversion and Systemic Bleeding Complications in Patients with Age-Related Macular Degeneration on Anticoagulants.

PURPOSE: Conversion to neovascular disease in patients with non-neovascular age-related macular degeneration (AMD) initiated on direct oral anticoagulants (DOACs) compared with matched patients treated with warfarin. DESIGN: Retrospective cohort study. PARTICIPANTS: The study included 20 300 patients and 13 387 patients with non-neovascular AMD initiated on DOACs or warfarin, respectively, before propensity score matching (PSM). METHODS: TriNetX was used to identify patients diagnosed with non-neovascular AMD stratified by treatment with DOACs or warfarin with at least 6 months of follow-up. Propensity score matching was performed to control for baseline demographics and medical comorbidities. MAIN OUTCOME MEASURES: Relative risk (RR) of developing neovascular AMD, macular hemorrhage (MH), vitreous hemorrhage (VH), and requiring an ocular intervention (intravitreal anti-VEGF therapy or pars plana vitrectomy [PPV]) within 6 months and 1 year. Patients with chronic atrial fibrillation (AF) on anticoagulation were separately evaluated for the same measures within 5 years after initiating therapy. RESULTS: Treatment with warfarin was associated with a higher risk of developing neovascular AMD at 6 months (RR, 1.24, 95% confidence interval [CI], 1.12-1.39; P < 0.001) and 1 year (RR, 1.26, 95% CI, 1.14-1.40; P < 0.001) when compared with matched patients treated with DOACs. There was an increased risk of requiring intravitreal anti-VEGF therapy (6 months: RR, 1.30; 95% CI, 1.13-1.49; P < 0.001; 1 year: RR, 1.31, 95% CI, 0.72-2.05; P < 0.001) and PPV (6 months: RR, 2.13; 95% CI, 1.16-3.94; P = 0.01; 1 year: RR, 2.29, 95% CI, 1.30-4.05; P = 0.003). Among patients with AMD and AF treated with warfarin, there was an increased risk of ocular complications (neovascular AMD: RR, 1.25; 95% CI, 1.14-1.38; P < 0.001; MH: RR, 1.86; 95% CI, 1.47-2.35; P < 0.001; VH: RR, 2.22; 95% CI, 1.51-3.26; P < 0.001) and need for intravitreal anti-VEGF therapy (RR, 1.34; 95% CI, 1.18-1.52; P < 0.001) over an extended 5-year period. There was no significant difference in the development of major systemic hemorrhagic events between the 2 cohorts over 5 years. CONCLUSIONS: Patients with non-neovascular AMD treated with warfarin were more likely to develop neovascular disease and require ocular intervention for hemorrhagic complications when compared with matched patients initiated on DOACs. FINANCIAL DISCLOSURE(S): Proprietary or commercial disclosure may be found after the references.

Association of Cutaneous Keloids, Hypertrophic Scarring, and Fibrosis with Risk of Postoperative Proliferative Vitreoretinopathy.

PURPOSE: To assess an association between cutaneous keloids, hypertrophic scarring, and fibrosis (KHF) and risk of postoperative proliferative vitreoretinopathy (PVR) after rhegmatogenous retinal detachment (RRD) repair. DESIGN: Retrospective, population-based cohort study. PARTICIPANTS: Patients aged ≥ 18 years who underwent initial retinal detachment (RD) repair with pars plana vitrectomy with or without scleral buckle (SB) (Current Procedural Terminology [CPT] 67108), pneumatic retinopexy (67110), and primary SB (67107) from January 1, 2003, to March 1, 2023. METHODS: A de-identified electronic health record database through TriNetX, a global health research network, was used to analyze patients. Patients were queried for International Classification of Diseases, 10th Revision (ICD-10) codes L91.0 (hypertrophic scar) and L90.5 (scar conditions and fibrosis of skin). Frequency of subsequent diagnosis of PVR (H35.2) and CPT codes for secondary surgery including complex RD repair (67113) were determined. Patients with proliferative diabetic retinopathy (PDR) (ICD-10 H10.35/H11.35) were excluded. Descriptive statistics (Z-test) and propensity score matching (PSM) were used to match for age, sex, and race. MAIN OUTCOME MEASURES: Prevalence of H35.2 and CPT 67113 within 180 days after RRD repair in the KHF cohort versus the non-KHF cohort. RESULTS: Among patients with CPT 67108, 1061 in each cohort (KHF and non-KHF) were analyzed after PSM. The mean (standard deviation) age was 60.7 (15.2) years. Within 180 days, 10.1% of patients in the KHF cohort and 3.4% in the non-KHF cohort had a diagnosis of PVR (H35.2) (P < 0.001, odds ratio [OR], 3.2; 95% confidence interval [CI], 2.13-4.71). A total of 8.3% of patients in the KHF cohort and 5.4% of patients in the non-KHF cohort underwent complex RD repair (CPT 67113) (P = 0.008; OR, 3.2; 95% CI, 1.13-2.25). When including all RD repair types (CPT 67108, 67110, 67107), the rate of PVR diagnosis was still significantly greater in the KHF cohort than in the non-KHF cohort (9.0% vs 4.2%, P < 0.01; OR, 2.28; 95% CI, 1.64-3.16). CONCLUSIONS: A dermatologic history of KHF may be a risk factor for PVR after RD repair. FINANCIAL DISCLOSURE(S): Proprietary or commercial disclosure may be found after the references.

The Biosimilar Paradox: How Anti-Vascular Endothelial Growth Factor Biosimilars Could Increase Patient and Overall Health Care Costs.

PURPOSE: Anti-vascular endothelial growth factor (VEGF) medications for intraocular use are a major and increasing cost, and biosimilars may be a means of reducing the high cost of many biologic medications. However, a bevacizumab biosimilar, which is currently pending Food and Drug Administration (FDA) approval (bevacizumab-vikg), paradoxically may increase the cost burden of intravitreal anti-VEGF agents, because off-label repackaged drugs may no longer be allowed per the Drug Quality and Security Act (DQSA). We aimed to investigate the potential impact of biosimilars on costs in the United States. DESIGN: Cost analysis of anti-VEGF medications. PARTICIPANTS: Medicare data from October 2022 and previously published market share data from 2019. METHODS: Average sales prices (ASPs) of ranibizumab, aflibercept, and bevacizumab were calculated from Medicare allowable payments. The ASPs of biosimilars were calculated from wholesale acquisition costs from a representative distributor. The cost of an intraocular bevacizumab formulation is modeled at $500/1.25-mg dose and $900/1.25-mg dose. MAIN OUTCOME MEASURES: Costs of anti-VEGF drugs to Medicare Part B and patients. RESULTS: If an intraocular bevacizumab biosimilar were to be priced at $500, costs to Medicare would increase by $457 million from $3.01 billion to $3.47 billion (15.2% increase). Patient responsibility would increase by $117 million from $768 million to $884 million. Similarly, if intraocular bevacizumab were priced at $900, Medicare costs would increase by $897 million to $3.91 billion (29.8% increase), and patient responsibility would increase by $229 million to $997 million. If bevacizumab were $500/dose, switching all patients currently receiving ranibizumab or aflibercept to respective biosimilars would compensate for only 28.8% of the increased cost. Current prices of ranibizumab and aflibercept biosimilars would have to decrease by an aggregate of 15.7% to $616.80/injection, $1027.97/injection, and $1436.88/injection for ranibizumab 0.3 mg, ranibizumab 0.5 mg, and aflibercept, respectively. CONCLUSIONS: An FDA-approved bevacizumab biosimilar for ophthalmic use could increase costs to the health care system and patients, raising concerns for access. This increase would not be offset by ranibizumab and aflibercept biosimilar use at current prices. These data support the need for an exemption of section 503B of the DQSA and continued use of repackaged off-label bevacizumab. FINANCIAL DISCLOSURE(S): Proprietary or commercial disclosure may be found in the Footnotes and Disclosures at the end of this article.

Intravitreal Pharmacotherapies for Diabetic Macular Edema: A Report by the American Academy of Ophthalmology.

PURPOSE: To review the evidence on the safety and efficacy of current anti-vascular endothelial growth factor (VEGF) and intravitreal corticosteroid pharmacotherapies for the treatment of diabetic macular edema (DME). METHODS: Literature searches were last conducted on May 13, 2020, in the PubMed database with no date restrictions and limited to articles published in English. The combined searches yielded 230 citations, of which 108 were reviewed in full text. Of these, 31 were deemed appropriate for inclusion in this assessment and were assigned a level of evidence rating by the panel methodologist. RESULTS: Only the 21 articles with level I evidence were included in this assessment. Seventeen articles provided level I evidence for 1 or more anti-VEGF pharmacotherapies, including ranibizumab (14), aflibercept (5), and bevacizumab (2) alone or in combination with other treatments for DME. Level I evidence was identified in 7 articles on intravitreal corticosteroid therapy for treatment of DME: triamcinolone (1), dexamethasone (4), and fluocinolone acetonide (2). CONCLUSIONS: Review of the available literature indicates that intravitreal injections of anti-VEGF agents and corticosteroids are efficacious treatments for DME. Elevated intraocular pressure and cataract progression are important potential complications of corticosteroid therapy. Further evidence is required to assess the comparative efficacy of these therapies. Given the limited high-quality comparative efficacy data, choice of therapy must be individualized for each patient and broad therapeutic access for patients is critical to maximize outcomes.

Proteomics in uveal melanoma.

PURPOSE OF REVIEW: This article reviews the latest proteomic research on uveal melanoma. RECENT FINDINGS: Proteomic analysis of uveal melanoma cell lines and tissue specimens has improved our understanding of the pathophysiology of uveal melanoma and helped identify potential prognostic biomarkers. Circulating proteins in patient serum may aid in the surveillance of metastatic disease. The proteomes of aqueous and vitreous biopsy specimens may provide safer biomarkers for metastatic risk and candidate therapeutic targets in uveal melanoma. Proteomic analysis has the potential to benefit patient outcomes by improving diagnosis, prognostication, surveillance, and treatment of uveal melanoma. SUMMARY: These recent findings demonstrate that proteomic analysis is an important area of research to better understand the pathophysiology of uveal melanoma and improve the personalized management of our patients.

Discontinuation and loss to follow-up rates in clinical trials of intravitreal anti-vascular endothelial growth factor injections.

PURPOSE: Clinical trials are often designed to include homogenous, highly specific patient populations with many resources to reduce patient dropout. Results may not translate to real-world settings. We evaluated discontinuation and loss to follow-up (LTFU) rates in clinical trials of anti-vascular endothelial growth factor (anti-VEGF) injections for diabetic macular edema (DME), age-related macular degeneration (AMD), and retinal vein occlusion (RVO). METHODS: Retrospective meta-epidemiological study. The authors queried ClinicalTrials.gov for all completed trials of anti-VEGF injections for DME, AMD, or RVO. Of 658 trials identified, 582 were excluded for being non-interventional, <100 patients, terminating early, or missing study results. The remaining 76 trials of 27,823 patients were analyzed for discontinuation and LTFU rates. RESULTS: Mean discontinuation rate was 12.44% (SD 8.12%, range 0-54.12%), with higher rates among control (18.87%) than treatment arms (10.78%, p = .006). Mean LTFU rate was 1.84% (SD 1.78%, range 0-7.76%), with no differences by disease, treatment type, or treatment frequency. CONCLUSION: Discontinuation rates of major intravitreal anti-VEGF clinical trials were highly variable, suggesting even trials struggle with overall patient retention. Though trial LTFU rates were low, real-world outcomes may differ due to higher reported LTFU rates, which should be considered when extrapolating trial results to clinical practice.

BILATERAL SERPIGINOUS-LIKE CHORIORETINITIS ASSOCIATED WITH CILIOCHOROIDAL MELANOMA: A Clinicopathologic Correlation.

PURPOSE: To report the clinicopathologic correlation of a case of bilateral serpiginous-like chorioretinitis (SLC) associated with unilateral ciliochoroidal melanoma. METHODS: A 71-year-old white woman was diagnosed with progressive SLC in both eyes associated with ciliochoroidal melanoma in the right eye. Clinical findings and imaging before and after enucleation in the right eye were correlated to histologic and immunohistochemistry sections. RESULTS: Examination and imaging identified a peripheral bilobed amelanotic lesion with low reflectivity on B-scan ultrasound with an associated exudative detachment in the right eye. Additionally, multiple areas of new SLC lesions in the macula and peripapillary region in the right eye and along the inferior arcade in the left eye were observed. Oncologic evaluation confirmed a Class 2, ciliochoroidal melanoma, and the eye was enucleated. Autoimmune and infectious laboratory evaluations for the etiology of the SLC lesions were negative. Histopathology of the enucleated eye confirmed the diagnosis of uveal melanoma with lymphocytic inflammation at the edges of the tumor itself and in the areas of discrete SLC lesions. Immunohistochemistry identified similar predominantly CD3 and CD8 T cells and fewer CD20 B cells in both regions. CONCLUSION: Serpiginous-like chorioretinitis may present as a paraneoplastic, predominantly T-lymphocyte inflammation associated with intraocular tumor such as uveal melanoma.

Response criteria for intraocular retinoblastoma: RB-RECIST.

Standardized guidelines for assessing tumor response to therapy are essential for designing and conducting clinical trials. The Response Evaluation Criteria In Solid Tumors (RECIST) provide radiological standards for assessment of solid tumors. However, no such guidelines exist for the evaluation of intraocular cancer, and ocular oncology clinical trials have largely relied on indirect measures of therapeutic response-such as progression-free survival-to evaluate the efficacy of treatment agents. Herein, we propose specific criteria for evaluating treatment response of retinoblastoma, the most common pediatric intraocular cancer, and emphasize a multimodal imaging approach for comprehensive assessment of retinoblastoma tumors in clinical trials.

Metastasis of Lung Adenocarcinoma to the Lacrimal Sac.

The authors report an unusual case of lung adenocarcinoma metastasis to the lacrimal sac. A 61-year-old woman with stage IV non-small cell lung cancer presented with left facial pain and epiphora. She was found to have an elevated tear meniscus associated with a firm, fixed medial canthal mass. Orbital imaging demonstrated nodular enlargement of the lacrimal drainage apparatus. Biopsy of the lacrimal sac was performed, and it revealed a metastatic lung adenocarcinoma. The patient received targeted radiation therapy to the lacrimal sac, and her dose of maintenance chemotherapy was increased. The patient's symptoms have since improved. This case of lung cancer involving the lacrimal sac highlights the importance of thorough oncologic surveillance, even with respect to locations atypical for metastatic spread.

Comparing clinical outcomes of macular hole surgeries performed by trainee surgeons using a 3D heads-up display viewing system versus a standard operating microscope.

PURPOSE: To compare the surgical outcomes of macular hole (MH) surgery performed by trainee surgeons using a three-dimensional heads-up display (3D HUD) versus a standard operating microscope (SOM). MATERIALS AND METHODS: A retrospective review of all consecutive medical records patients operated on for MHs by a trainee surgeon between 2017 and 2020 using either 3D HUD or SOM was performed. Minimum hole diameter, maximum hole diameter, total surgical time, and MH closure rates were compared between the two groups. MH retinal detachments, traumatic MHs, and MHs for which inverted internal limiting membrane flaps were used were excluded from the study. RESULTS: Trainee surgeons operated on 51 patients using 3D HUD and 63 patients using SOM. Age at presentation, intraocular pressure (IOP) at diagnosis, maximum hole diameter, minimum hole diameter, surgical time, duration between diagnosis and surgery were comparable between both groups. MH closure rate was significantly (p < 0.004) higher in the 3D HUD group (n = 44, 86.3%) than that of the SOM group (n = 38, 60.3%). There were no postoperative adverse events such as glaucoma or retinal detachment in either group. Other than the viewing technique, there were no significant variables associated with MH closure in the two groups. CONCLUSION: Surgeries conducted by trainee surgeons using 3D HUD had higher MH closure rates than those using SOM.

Ophthalmic Medication Expenditures and Out-of-Pocket Spending: An Analysis of United States Prescriptions from 2007 through 2016.

PURPOSE: To estimate temporal trends in total and out-of-pocket (OOP) expenditures for ophthalmic prescription medications among adults in the United States. DESIGN: Retrospective, longitudinal cohort study. PARTICIPANTS: Participants in the 2007 through 2016 Medical Expenditure Panel Survey (MEPS) 18 years of age or older. The MEPS is a nationally representative survey of the noninstitutionalized, civilian United States population. METHODS: We estimated trends in national and per capita annual ophthalmic prescription expenditures by pooling data into 2-year cycles and using weighted linear regressions. We also identified characteristics associated with greater total or OOP expenditures with multivariate weighted linear regression. Costs were adjusted to 2016 United States dollars using the gross domestic product price index. MAIN OUTCOME MEASURES: Trends in total and OOP annual expenditures for ophthalmic medications from 2007 through 2016 as well as factors associated with greater expenditures. RESULTS: From 2007 through 2016, 9989 MEPS participants (4.2%) reported ophthalmic medication prescription use. Annual ophthalmic medication use increased from 10.0 to 12.2 million individuals from 2007 and 2008 through 2015 and 2016. In this same period, national expenditures for ophthalmic medications increased from $3.39 billion to $6.08 billion and OOP expenditures decreased from $1.34 to $1.18 billion. Per capita expenditure increased from $338.72 to $499.42 (P < 0.001), and per capita OOP expenditure decreased from $133.48 to $96.67 (P < 0.001) from 2007 and 2008 through 2015 and 2016, respectively. From 2015 through 2016, dry eye (29.5%) and glaucoma (42.7%) medications accounted for 72.2% of all ophthalmic medication expenditures. Patients who were older than 65 years (P < 0.001), uninsured (P < 0.001), and visually impaired (P < 0.001) were significantly more likely to have greater OOP spending on ophthalmic medications. CONCLUSIONS: Total ophthalmic medication expenditure in the United States increased significantly over the last decade, whereas OOP expenses decreased. Increases in coverage, copayment assistance, and use of expensive brand drugs may be contributing to these trends. Policy makers and physicians should be aware that rising overall drug expenditures ultimately may increase indirect costs to the patient and offset a decline in OOP prescription drug spending.

Multi-center analysis of intraocular biopsy technique and outcomes for uveal melanoma: Ocular Oncology Study Consortium report 4.

PURPOSE: To investigate the relationship between surgical approach for intraocular tumor biopsy of uveal melanoma and tumor morphologic features such as size and intraocular location and the effect of these variables on diagnostic yield and biopsy outcome. METHODS: Consecutive patients from nine Ocular Oncology centers with uveal melanoma (UM) undergoing tumor biopsy immediately preceding I125 plaque brachytherapy with tissue sent for gene expression profiling (GEP) testing were reviewed retrospectively. RESULTS: Three hundred sixty patients were included (50% men, mean age 60.2 years). Overall biopsy yield was 99% and 83% for GEP and cytopathology, respectively. Surgeon choice of biopsy approach (trans-vitreal vs. trans-scleral) was found to associate with both tumor location and tumor thickness. A trans-scleral rather than trans-vitreal approach was used more commonly for anteriorly located tumors (92% vs. 38% of posterior tumors, p < 0.001) and thicker tumors (86% vs. 55% of thin tumors, p < 0.001). When performing trans-vitreal biopsies, ocular oncologists with previous vitreoretinal surgery fellowship training were more likely to use wide-field surgical viewing systems, compared with indirect ophthalmoscopy (82.6% vs. 20.6%, p < 0.001). Surgical complications were rare and occurred more frequently with trans-vitreal biopsies (3.6% vs. 0.46%, p = 0.046). CONCLUSIONS: In this multi-center analysis of UM tumor biopsy, surgical yield was high for obtaining tumor tissue for GEP and cytopathology analysis with both trans-scleral and trans-vitreal techniques. Fellowship-trained ocular oncologists' preferred intraocular biopsy techniques associated strongly with tumor location, tumor thickness, and fellowship training of the surgeon. Short-term complication rates were low.

CORRELATION OF GENE EXPRESSION PROFILE STATUS AND AMERICAN JOINT COMMISSION ON CANCER STAGE IN UVEAL MELANOMA.

PURPOSE: To study the relationship between gene expression profile (GEP) subclass and American Joint Committee on Cancer (AJCC) stage in patients with uveal melanoma (UM). METHODS: A retrospective, multicenter study was undertaken with patients entered from nine major ocular oncology centers from across the United States. Three hundred sixty eligible patients had UM and underwent I-125 plaque brachytherapy with concurrent tumor biopsy with GEP testing between January 1, 2010, and October 28, 2014. Patient demographics and UM features were analyzed by both GEP and AJCC status. RESULTS: Gene expression profile class divided the cohort into three groups: Class 1a (n = 186), Class 1b (n = 77), and Class 2 (n = 113). When classified using AJCC staging criteria, we found the following: Stage I in 91 cases (25.3%), Stage IIA in 143 cases (39.7%), Stage IIB in 89 cases (24.7%), Stage IIIA in 36 cases (10%), and Stage IIIB in 1 case (0.3%). There were no Stage IV cases, as lymph node and metastatic data were not collected as a part of this study. Among Stage I tumors, both high tumor height and high largest basal diameter were associated with a higher frequency of Class 2 status (P < 0.05). As UMs progress to a larger AJCC tumor group (T1-T4), the odds ratio of having a worse prognosis based on GEP class was 1.75 (95% CI, 1.36-2.25; P < 0.001). Similarly, as UMs progress to a higher AJCC stage, the odds ratio of having a worse prognosis based on GEP class was 1.69 (95% CI, 1.36-2.10; P < 0.001). CONCLUSION: This report details the differences in clinical features between GEP subclasses and how they are distributed among the AJCC stages. When the tumors were grouped by AJCC staging criteria, both larger AJCC tumor (T) group and worsening AJCC stage were associated with worsening predicted prognosis, based on GEP subclass.

Pseudoprogression of Metastatic Melanoma to the Orbit With Pembrolizumab.

The management of metastatic melanoma to the orbit may involve a variety of therapeutic modalities including external-beam radiation, chemotherapy, and varying degrees of surgical resection or debulking. Pembrolizumab is an immunotherapeutic agent that has demonstrated efficacy in the treatment of metastatic melanoma. The authors present a case of metastatic melanoma to the orbit demonstrating profound pseudoprogression within hours of beginning pembrolizumab therapy, with associated mass effect and vision loss. Systemic corticosteroids, orbital external-beam radiation therapy, and a brief interruption in pembrolizumab halted expansion of the orbital lesion and vision loss. This case illustrates that rapid increase in orbital melanoma size, due to acute inflammatory response, may occur after initiation of systemic pembrolizumab therapy. Clinicians should be aware of this pseudoprogression mechanism as a potential cause of vision compromise in metastatic orbital melanoma. Prompt recognition and treatment may be needed to prevent permanent vision loss.

The Effect of Anti-Vascular Endothelial Growth Factor Agents on Intraocular Pressure and Glaucoma: A Report by the American Academy of Ophthalmology.

PURPOSE: To assess the effect of intravitreal injections of anti-vascular endothelial growth factor (VEGF) agents on immediate and long-term intraocular pressure (IOP) elevation and glaucoma. METHODS: Literature searches of the PubMed and Cochrane databases, last conducted in April 2018, yielded 253 unique citations. Of these, 41 met the inclusion criteria and were rated according to the strength of evidence. Two articles were rated level I, 17 were rated level II, and 15 were rated level III; an additional 7 were excluded because of poor study design and lack of relevance to the topic under evaluation. RESULTS: The studies that reported on short-term IOP elevation (i.e., between 0 and 60 minutes) showed that an immediate increase in IOP is seen in all patients when measured between 0 and 30 minutes of intravitreal injection and that the IOP elevation decreases over time. The data on long-term IOP elevation were mixed; 7 studies reported that between 4% and 15% of patients developed sustained elevation of IOP at 9 to 24 months after injection, whereas 6 studies found no long-term change in IOP from 1 to 36 months after injection. Pretreatment with glaucoma medications, anterior chamber tap, vitreous reflux, longer intervals between injections, and longer axial lengths were associated with lower IOP elevations after injection. Data were mixed on the relationship between IOP increase and the type of intravitreal injection, number of intravitreal injections, preexisting glaucoma, and globe decompression before injection. There were no data on the onset or progression of glaucoma in the studies reviewed in this assessment. CONCLUSIONS: Intravitreal injection of anti-VEGF agents results in an immediate and transient increase in IOP. A long-term increase in IOP also may be seen, and further studies are needed to determine at-risk populations. Although there is some suggestion in the literature, there is currently insufficient data to determine the impact of intravitreal anti-VEGF injections on glaucoma progression. Although pretreatment with glaucoma medications, performing anterior chamber paracentesis, or increasing the interval between injections may reduce the impact of transient IOP elevation, the clinical significance and associated risks of these interventions are unknown.

RELATIONSHIP OF CLINICAL FEATURES AND BASELINE TUMOR SIZE WITH GENE EXPRESSION PROFILE STATUS IN UVEAL MELANOMA: A Multi-institutional Study.

PURPOSE: To study the relationship between gene expression profile subclass and clinical features in a multicenter cohort of patients with uveal melanoma. METHODS: A retrospective, multicenter study was undertaken with patients entered from nine major ocular oncology centers from across the United States. Eligible patients had uveal melanoma and underwent I-125 plaque brachytherapy with concurrent tumor biopsy with gene expression profile testing between January 1, 2010, and October 28, 2014. Data were collected regarding patient demographics, baseline tumor clinical features, and gene expression profile results. Statistical analyses were performed using the Fisher's exact test, Wilcoxon rank-sum test, Kruskal-Wallis test, and proportional-odds cumulative logit modeling. RESULTS: Inclusion criteria were met for 379 patients. Gene expression profile class divided the cohort into two main groups, Class 1 (n = 263) and Class 2 (n = 113). Class 1 tumors were further subdivided into Class 1a (n = 186) and Class 1b (n = 77). The differences between Class 1 and Class 2 tumors were similar to previous studies, except the finding of Class 2 tumors being more likely to have associated exudative retinal detachment (P < 0.001). There was no statistically significant difference between Class 1 and Class 2 tumors based on the presence of lipofuscin, drusen, or subretinal fluid. Class 1a tumor patients, compared with Class 1b, were significantly older (P = 0.034). Class 2 tumors, when compared with Class 1b, were associated with increasing patient age (P < 0.001), larger tumor height (P = 0.010), ciliary body involvement (P = 0.001), exudative retinal detachment (P = 0.024), and anterior tumor location (P < 0.001). When the tumors were grouped into Collaborative Ocular Melanoma Study size categories, increasing tumor size category was significantly associated with Class 2 status: 6% of small tumors, 32% of medium tumors, and 53% of large tumors were Class 2. CONCLUSION: In a multi-institutional setting, we found that the only significant difference in clinical features between Class 1a and Class 1b tumors was that patients with Class 1a tumors were older at the time of diagnosis. We also found that Class 1a and Class 1b have clinical features distinct from Class 2 tumors. The distribution of the gene expression profile subclasses among the size groups was similar to reported time-to-metastasis data among the same size groupings. Our clinical findings support the current molecular classification-based survival data previously reported in uveal melanoma.

IDENTIFICATION OF POSTERIOR SEGMENT PATHOLOGY WITH EN FACE RETINAL IMAGING USING MULTICOLOR CONFOCAL SCANNING LASER OPHTHALMOSCOPY.

PURPOSE: To assess posterior segment findings on multicolor confocal scanning laser ophthalmoscopy by correlation with spectral domain optical coherence tomography (SD-OCT) and to quantify agreement between these imaging modalities. METHODS: Retrospective review of 159 eyes of 96 consecutive patients who underwent concurrent imaging with multicolor confocal scanning laser ophthalmoscopy and SD-OCT. Positive percent agreement and negative percent agreement were calculated for each finding identified on infrared, green, blue, and multicolor reflectance images using SD-OCT as a comparator. RESULTS: Infrared reflectance best detected outer retinal and choroidal findings such as choroidal lesions, retinal pigment epithelium atrophy, peripapillary atrophy, and drusen (positive percent agreement 100, 92, 92, and 67%, respectively). Inner retinal changes including epiretinal membrane, lamellar macular hole, and inner retinal alterations were best detected on blue reflectance (positive percent agreement 94, 50, and 100%, respectively). Composite multicolor reflectance most effectively detected conditions with retinal elevation, including pigment epithelial detachment, intraretinal fluid, and subretinal fluid (positive percent agreement 65, 49, and 54%, respectively). Multicolor confocal scanning laser ophthalmoscopy detected intraretinal and subretinal hemorrhages, which were not detected on SD-OCT (negative percent agreement 87 and 97%, respectively). CONCLUSION: Multicolor confocal scanning laser ophthalmoscopy is capable of identifying posterior segment pathology at various anatomical depths and may be a useful adjunct to SD-OCT for detecting or monitoring certain retinal conditions.